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Title: Confocal laser endomicroscopy in the assessment of intestinal permeability in acute and chronic pancreatitis
Author: Bharucha, S.
ISNI:       0000 0004 7656 8495
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2019
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Background: The function of the gastrointestinal tract in monitoring and sealing the host interior from toxins, antigens and microbes, is termed the gut barrier. Disruptions in the gut barrier result in an increase in intestinal permeability (IP). Evidence suggests that the intestinal permeability barrier becomes compromised in acute pancreatitis (AP), chronic liver disease (CLD) and to a limited degree in chronic pancreatitis (CP). In acute pancreatitis, changes correlate with disease severity, multi-organ failure, mortality and outcome. Bacterial translocation and dysbiosis along with immunological responses have also been associated with changes in gut permeability. Confocal laser endomicroscopy (CLE) is a novel tool that has been used to investigate intestinal permeability in other gastrointestinal disease. Aims: To determine whether CLE can be used to assess intestinal permeability, bacterial translocation and endotoxaemia in patients with chronic pancreatitis, chronic liver disease and acute pancreatitis. To assess the responses of immunology and infection in patients with acute pancreatitis whilst also assessing changes related to increasing severity of disease in acute pancreatitis. Methods: 182 patients were recruited: 54 AP (Determinant Based Classification); 47 CP (surgically or conservatively managed); 33 CLD and 48 non-ulcer dyspepsia, rendering 13 healthy controls. Blood was sampled and duodenal fluid aspirated for culture. CLE was performed in consenting patients and fluorescein leakage scored. Endotoxin antibodies, cytokine concentrations and lactulose mannitol ratios were measured; Diamine oxidase (DAO) concentrations were assayed in AP patients undergoing CLE. Results: Fluorescein leakage and lactulose mannitol ratios were significantly higher in patients with AP (p=0.0346 and p=0.046 respectively) and surgically managed CP (p=0.032, p=0.030) compared to healthy controls. Patients with AP more frequently showed positive duodenal bacterial cultures than controls (p=0.004); positive duodenal cultures were associated with fluorescein leakage (p=0.035). Plasma endotoxin antibody concentrations were decreased in AP compared to controls. Multiple cytokines showed significantly increased concentrations in severe AP. DAO concentrations were significantly increased in AP patients who showed fluorescein leakage at CLE (p=0.035). Conclusion: CLE identified increased IP in AP and surgically managed CP, associated with endotoxaemia, increased serum cytokines and DAO, with most marked changes in severe AP. The association of fluorescein leakage with duodenal bacterial proliferation in AP indicates major gut dysfunction that may account for bacterial translocation via epithelial gaps, contributing to AP severity. Endotoxaemia, positive duodenal bacterial cultures, and increased serum concentrations of several cytokines were associated with increasing severity of AP. The increase in positive duodenal bacterial cultures in patients who also demonstrated fluorescein leakage at CLE supports a hypothesis of bacterial translocation, suggesting that the gastrointestinal barrier is altered in AP. Evidence for increased IP was also observed in surgically managed CP patients, suggesting that the gut barrier may also be compromised in some CP patients.
Supervisor: Sutton, Robert ; Pritchard, Mark Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral